Abstract Women constitute a majority of the patients with epilepsy, and many of them experience a cyclical exacerbation of seizures related to periodic changes in serum progesterone and estrogen levels during the menstrual cycle. This condition is called catamenial epilepsy. Currently, there are no scientifically tested effective treatments for catamenial exacerbation. In a multi-center trial of progesterone therapy for catamenial epilepsy failed to show efficacy. We have developed a model of chronic temporal lobe epilepsy in female rats and will use this model to study the effect of prolonged progesterone exposure on excitatory and inhibitory synaptic transmission and on seizure frequency and intensity. Specifically, we will test our hypothesis that a chronic elevation of progesterone in female animals diminishes the anticonvulsant action of progesterone by enhancing AMPA receptor-mediated glutamatergic synaptic transmission and suppressing GABAA receptor mediated synaptic transmission. In Aim 1, we will determine the impact of progesterone treatment on glutamatergic synaptic transmission on hippocampal principal neurons in nave and epileptic female rats using a combination of patch clamp electrophysiology and analysis of the expression of the AMPA receptor subunits via both biochemical and immunohistochemical techniques. In Aim 2, we will determine the impact of progesterone treatment on GABAergic synaptic transmission on hippocampal principal neurons of nave and epileptic female rats with a similar combination of techniques as in aim 1. In Aim 3, we will determine the role of progesterone receptors in progesterone-induced tolerance during progesterone treatment and withdrawal. These studies will provide novel insights into the mechanisms of catamenial epilepsy. These studies could explain the mechanism of failure progesterone therapy for treatment of catamenial epilepsy and potentially identify novel therapeutic targets for the treatment of catamenial exacerbation of seizures.